The main objective of this renewal proposal is to devise the optimal means to specifically suppress the production of antibodies to nucleic acids in murine lupus. In view of the importance of complexes of antibodies to nucleic acids with nucleic acids in the disease, we propose to induce immunologic tolerance to nucleic acid antigens. Our long-term goal is to develop immunotherapy as a treatment for lupus. To achieve this goal, two complementary means will be used. First, tolerogens made of nucleic acid antigens covalently linked to isologous IgG will be used to induce immunologic tolerance. Second, tolerogens made of nucleic acid antigens bound to lymphoid cells (isogeneic spleen cells) will be used to induce specific immune suppression. The first approach induces predominantly B cell tolerance; the second generates suppressor T cells. Thus, whether the ultimate cause of autoimmunity in SLE is either a T cell or B cell defect or both, each approach is a specific means of manipulating an arm of the immune system. The ability to generate suppressor cells relevant to an autoantigen that causes tissue damage, such as nucleic acid, will allow us to determine the role of nucleic acid-specific suppressor T cells in the pathogenesis of murine SLE, and whether or not the generation of T cells that suppress the formation of antibodies to nucleic acids has therapeutic value. We will also attempt to make T cell hybridomas that generate antigen-specific suppressor factors in vitro, and use these suppressor factors to treat the disease. Although our primary goal is to apply the principle of tolerance therapeutically, two important aims of this proposal are to elucidate further the cellular mechanisms and the genetics of tolerance and suppression. For example, we have found that adult thymectomy prevents suppression without impairing tolerance, which indicates that the cellular mechanism underlying the induction of suppressor cells is distinct from that underlying tolerance. We have also found that NZW mice are resistant, whereas NZB mice are susceptible, to nucleoside specific immune suppression. We will, therefore, test the hypothesis that the abnormal production of autoantibody to nucleic acid antigens in BWF1 is due to a genetic defect in the generation of suppressor cells.